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Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs.

ABSTRACT: Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a negatively charged surface on the enzyme to interact with the histone tail.

SUBMITTER: Karukurichi KR

PROVIDER: S-EPMC3076313 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs.

Karukurichi Kannan R KR Cole Philip A PA

Bioorganic chemistry 20101028 1

Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biological pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and t ...[more]

PMID: 21111442

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